Research Papers:

Interleukin-6 expression contributes to lapatinib resistance through maintenance of stemness property in HER2-positive breast cancer cells

Wei-Chien Huang, Chao-Ming Hung, Ching-Ting Wei, Tsung-Ming Chen, Pei-Hsuan Chien, Hsiao-Lin Pan, Yueh-Ming Lin and Yun-Ju Chen _

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Oncotarget. 2016; 7:62352-62363. https://doi.org/10.18632/oncotarget.11471

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Wei-Chien Huang1,2,3,4, Chao-Ming Hung5,6, Ching-Ting Wei5,6,*, Tsung-Ming Chen7,*, Pei-Hsuan Chien8, Hsiao-Lin Pan5, Yueh-Ming Lin9, Yun-Ju Chen5,8,10

1The Ph.D. program for Cancer Biology and Drug Discovery, China Medical University and Academia Sinica, Taichung 404, Taiwan

2Graduate Institute of Cancer Biology, China Medical University, Taichung 404, Taiwan

3Center for Molecular Medicine, China Medical University and Hospital, Taichung 404, Taiwan

4Department of Biotechnology, Asia University, Taichung 413, Taiwan

5School of Medicine for International Students, I-Shou University, Kaohsiung 824, Taiwan

6Department of General Surgery, E-Da Hospital, Kaohsiung 824, Taiwan

7Department and Graduate Institute of Aquaculture, National Kaohsiung Marine University, Kaohsiung 811, Taiwan

8Department of Medical Research, E-Da Hospital, Kaohsiung 824, Taiwan

9Division of Colorectal Surgery, Department of Surgery, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 833, Taiwan

10Department of Biological Science & Technology, I-Shou University, Kaohsiung 824, Taiwan

*These authors have contributed equally to this work

Correspondence to:

Yun-Ju Chen, email: [email protected]

Keywords: lapatinib, interleukin-6, HER2, resistance, breast cancer

Received: February 10, 2016     Accepted: August 09, 2016     Published: August 22, 2016


Lapatinib is an inhibitor of human epidermal growth factor receptor 2 (HER2), which is overexpressed in 20-25% of breast cancers. Clinically, lapatinib has shown promising benefits for HER2-positive breast cancer patients; however, patients eventually acquire resistance, limiting its long-term use. In a previous study, we found that interleukin-6 (IL-6) production was increased in acquired lapatinib-resistant HER2-positive breast cancer cells. In the present study, we confirmed that lapatinib-resistant cells had elevated IL-6 expression and also maintained both stemness population and property. The increase in IL-6 was required for stemness property maintenance, which was mediated primarily through the activation of signal transducer and activator of transcription 3 (STAT3). Blocking IL-6 activity reduced spheroid formation, cell viability and subsequently overcame lapatinib resistance, whereas stimulation of IL-6 rendered parental cells more resistant to lapatinib-induced cytotoxicity. These results point to a novel mechanism underlying lapatinib resistance and provide a potential strategy to overcome resistance via IL-6 inhibition.

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